Piperidinylalkyl quinazoline compounds, composition and method of use

ABSTRACT

Novel quinazoline derivatives, comprising in the heterocyclic part of their quinazoline nucleus at least one carbonyl or thiocarbonyl group and a particularly substituted piperidinyl-alkyl side chain, said compounds being potent serotonin-antagonists.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of our copending applicationSer. No. 1,493, filed Jan. 8, 1979, now abandoned.

BACKGROUND OF THE INVENTION

There are known in the art a number of pharmacologically activequinazolinones which are substituted on their heterocyclic ring with apiperidinylalkyl side chain. Such compounds may be found in thefollowing references:

U.S. Pat. Nos. 3,322,766; 3,528,982; 3,635,976; 3,812,257; 3,865,827;4,096,144; and 4,099,002;

Fr. Pat. No. 1,431,815; and

J. Med. Chem., 8, 807 (1965).

The compounds of the present invention differ from the foregoingessentially by the presence of particular substituent groups on thepiperidine ring of the piperidinyl-alkyl side chain.

In U.S. Pat. No. 4,035,369 there are described a series of1-(benzazolylalkyl)-4-substituted piperidines, from which the subjectcompound of this invention differ essentially by the replacement of thebenzazole group by a quinazoline group.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention is concerned with a novel series of quinazolinederivatives which are structurally represented by the formula ##STR1##and the pharmaceutically acceptable acid addition salts thereof,wherein:

Ar is an aryl radical;

X is a member selected from the group consisting of ##STR2## whereinsaid R_(a) is hydrogen or lower alkyl and said q is the integer 2 or 3;

R is a member selected from the group consisting of hydrogen, hydroxyand lower alkyl;

Alk is an alkylene chain having from 1 to 4 carbon atoms; and

Q is a quinazolinyl radical, the 1-, 2-, 3- or 4-position of which isconnected with the alkylene side chain, said quinazolinyl radicalbearing in one or both of its 2- and 4-positions a carbonyl orthiocarbonyl group, wherein the benzene ring of said quinazolinylradical is optionally substituted with 1 to 3 substituents eachindependently selected from the group consisting of halo, lower alkyl,lower alkyloxy, trifluoromethyl, nitro and cyano, and wherein thepyrimidino ring of said quinazolinyl radical may be partly or fullysaturated, said pyrimidino ring being optionally substituted with 1 to 3substituents independently selected from the group consisting of loweralkyl, aryl and aryl(lower alkyl);

wherein said aryl as used in the definition of said Ar and of said Q isa member selected from the group consisting of phenyl, substitutedphenyl, thienyl and pyridinyl, wherein said substituted phenyl has from1 to 3 substituents each independently selected from the groupconsisting of halo, lower alkyl, lower alkyloxy, trifluoromethyl andamino.

As used in the foregoing definitions the term "lower alkyl" is meant toinclude straight and branched hydrocarbon radicals having from 1 to 6carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl,1,1-dimethylethyl, propyl, butyl, pentyl, hexyl and the like; "alkylene"as used in the definition of Alk comprises straight and branchedalkylene chains having from 1 to 4 carbon atoms; and the term "halo" isgeneric to fluoro, chloro, bromo and iodo.

Examples of quinazolinyl radicals within the scope of Q are optionallysubstituted 1,4-dihydro-2,4-dioxo-3(2H)-quinazolinyl,3,4-dihydro-2,4-dioxo-1(2H)-quinazolinyl,3,4-dihydro-4-oxo-1(2H)-quinazolinyl,1,2,3,4-tetrahydro-4-oxo-2-quinazolinyl,1,4-dihydro-4-oxo-3(2H)-quinazolinyl and the like radicals.

Preferred compounds within the scope of formula (I) are those wherein Xrepresents CO. Particularly preferred compounds are those wherein X isCO and Alk represents an 1,2-ethanediyl radical. The compound3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedioneis especially preferred.

The compounds of formula (I) have basic properties and, consequently,they may be converted to their therapeutically active non-toxic acidaddition salt forms by treatment with appropriate acids, such as, forexample, inorganic acids, such as hydrohalic acid, e.g., hydrochloric,hydrobromic and the like, and sulfuric acid, nitric acid, phosphoricacid and the like; or organic acids, such as, for example, acetic,propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic,propanedioic, butanedioic, (Z)-2-butanedioic, (E)-2-butenedioic,2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, benzoic, 3-phenyl-2-propenoic,α-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be converted by treatment with alkali intothe free base form.

The compounds of formula (I) can generally be prepared by the reactionof an appropriate reactive ester of the formula (II), wherein Q and Alkare as previously defined and W is a reactive ester residue such as, forexample, halo, particularly chloro, bromo or iodo, or a sulfonyloxyradical such as methylsulfonyloxy, 4-methylphenylsulfonyloxy and thelike, with an appropriate piperidine derivative of the formula (III)wherein R, X and Ar have the previously defined meanings. ##STR3##

The foregoing reaction may be carried out following standardN-alkylating procedures. Said reaction is preferably carried out in anappropriate reaction-inert organic solvent such as, for example, a loweralkanol, e.g., methanol, ethanol, propanol, butanol and the likealkanols; an aromatic hydrocarbon, e.g., benzene, methylbenzene,dimethylbenzene, and the like; an ether, e.g., 1,4-dioxane,1,1'-oxybispropane and the like; a ketone, e.g., 4-methyl-2-pentanone;N,N-dimethylformamide; nitrobenzene; and the like. The addition of anappropriate base such as, for example, an alkali or earth alkaline metalcarbonate or hydrogen carbonate, may be utilized to pick up the acidwhich is liberated during the course of the reaction. A small amount ofan appropriate metal iodide, e.g., sodium or potassium iodide may beadded as a reaction promotor. Somewhat elevated temperatures areappropriate to enhance the rate of the reaction and preferably thereaction is carried out at the reflux temperature of the reactionmixture.

The compounds of formula (I) may also be prepared starting from acorresponding intermediate of the formula (IV) ##STR4## wherein Alk, R,X and Ar are as previously defined and Q' is an appropriate precursor ofQ, by converting said Q' into said Q following art-known procedures.Such procedures are described, for example, in "The Chemistry ofHeterocyclic Compounds-Fused Pyrimidines; Part I: Quinazolines", Ed. D.J. Brown, Interscience Publishers; New York, London, Sidney (1967), p.74-102 and p. 116-128. Examples of such conversions of Q' into Q aregiven hereafter.

In order to simplify the structural representation of the compounds offormula (I) and of certain precursors and intermediates thereof theappropriately substituted piperidinylalkyl radical of the formula##STR5## will hereinafter be represented by the symbol D.

The compounds of formula (I) wherein Q represents a1,2,3,4-tetrahydro-4-oxo- or 4-thioxo-quinazolinyl radical, saidcompounds being represented by the formula (I-a), can be prepared bycyclizing an appropriately substituted 2-aminobenzamide or-benzenethioamide of formula (IV-a) with an appropriately substitutedcarbonyl or thiocarbonyl compound of formula (V). In the followingreaction-equation one of R², R³, R⁴ and R⁵ is D, each of the remainingbeing independently selected from the group consisting of hydrogen,lower alkyl, aryl and aryllower alkyl; R¹ is selected from the groupconsisting of halo, lower alkyl, lower alkyloxy, trifluoromethyl, nitroand cyano; each Y is O or S; and n is an integer of from 0 to 3inclusive. ##STR6##

Said cyclization-reaction may conveniently be carried out by stirringthe reactants together in the presence of an appropriate solvent suchas, for example, a lower alkanol, e.g., methanol, ethanol, propanol andthe like. Somewhat elevated temperature and the addition of a catalyticamount of an appropriate strong acid, e.g., 4-methylbenzenesulfonicacid, hydrochloric acid and the like, may be used to enhance the rate ofthe reaction. Most preferably the reaction is carried out at the refluxtemperature of the reaction mixture. In the foregoing reaction thereagent of formula (V) may be replaced by an appropriate functionallyequivalent derivative thereof such as, for example, a di(loweralkyl)actal, a cyclic acetal and the like.

The compounds of formula (I) wherein Q represents a3,4-dihydro-4-oxo-2-quinazolinyl radical, a 4-oxo-3(4H)-quinazolinylradical or a corresponding thioxo analog thereof, said compounds beingrepresented by the formula (I-b), can be derived from an appropriatelysubstituted 2-aminobenzamide or -benzenethioamide of formula (IV-a)wherein R³ is hydrogen, (IV-a-1), by converting (IV-a-1) into thecorresponding 2-(acylamino)benzamide or -benzenethioamide of formula(VI) and cyclizing the latter following art-known cyclizing procedures.In the following reaction-equations either of R² and R⁴ is D, the otherbeing a member selected from the group consisting of hydrogen, loweralkyl, aryl and aryllower alkyl. ##STR7##

The foregoing cyclization reaction may be carried out by stirring andheating, preferably refluxing, the 2-(acylamino)benzamide or-benzenethioamide (VI) in a suitable reaction-inert solvent such as, forexample, a lower alkanol, e.g., methanol, ethanol, 2-propanol and thelike; an aliphatic or aromatic hydrocarbon, e.g., hexane, benzene,methylbenzene and the like; a halogenated hydrocarbon, e.g.,trichloromethane and the like. In order to enhance the rate of thereaction there may be added an appropriate base such as, for example, analkali or earth alkaline earth hydroxide, carbonate orhydrogencarbonate, e.g., sodium hydroxide, potassium carbonate, sodiumhydrogen carbonate and the like. The conversion of the 2-aminobenzamideor -benzenethioamide (IV-a-1) into the 2-(acylamino)benzamide or-benzenethioamide (VI) may be carried out by reacting (IV-a-1) with anappropriate acylating agent derived from the acid ##STR8## wherein R⁴has the previously defined meaning. Appropriate acylating agents includeanhydride and acyl halides derived from (VII). The acid (VII) itself mayoptionally be used as an acylating agent. In the latter case it isappropriate to remove the water formed during the course of the reactionby azeotropic distillation.

The compounds of formula (I) wherein Q is a1,4-dihydro-2,4-dioxo-3(2H)-quinazolinyl radical, a3,4-dihydro-2,4-dioxo-1(2H)-quinazolinyl radical or a mono- or dithioxoderivative thereof, said compounds being represented by the formula(I-c), may be derived from an appropriate 2-aminobenzamide or-benzenethioamide of formula (IV-a), by cyclizing the latter with urea,thiourea or a functionally equivalent derivative thereof. In thefollowing reaction scheme one of R² and R³ is D, the remaining beingselected from the group consisting of hydrogen, lower alkyl, aryl andaryllower alkyl, R¹ and n are as previously described and each Y isindependently selected from the group consisting of O and S. ##STR9##

Said cyclization may be carried out by stirring the reactants together,preferably at an elevated temperature and, if desired, in the presenceof an appropriate solvent such as, for example, an aromatic hydrocarbon,e.g., benzene and the like, a cyclic ether, e.g., tetrahydrofuran andthe like. A suitable derivative of urea and thiourea are, for example,1,1'-bis[1H-imidazol-1-yl]methanone and its corresponding thione.

The compounds of formula (I-c) may also be prepared by cyclizing anappropriately substituted compound of formula (IV-b) with an appropriateprimary amine of the formula (VIII). In the following reaction-scheme,Y, R¹ and n have the previously defined meanings, one of R² and R³ is D,the other hydrogen, lower alkyl or aryllower alkyl and R⁶ and R⁶ _(a)each represent an appropriate leaving group such as, for example, loweralkyloxy, amino and mono- and di(lower alkyl)amino. ##STR10##

The compounds of formula (I-c) wherein R³ is hydrogen and R² is D, saidcompounds being represented by the formula (I-c-1), can also be preparedby cyclizing an isocyanate or an isothiocyanate of formula (IV-c) with aprimary amine of formula (VIII) wherein R² is D, (VIII-a). In thefollowing reaction-equation R⁶ represents an appropriate leaving groupand R¹, n and Y are as previously described. ##STR11##

The compounds of formula (I-c) wherein R³ is D and R² is hydrogen, saidcompounds being represented by the formula (I-c-2), can also be preparedby cyclizing an appropriately substituted benzenamine orbenzenethioamine of formula (IV-d), wherein D, Y and R⁶ are aspreviously described, with an alkali metal cyanate or thiocyanate, e.g.,potassium cyanate, sodium thiocyanate and the like. ##STR12##

Said cyclization-reactions are conveniently carried out by stirring andheating the reactants together, optionally in a suitable reaction-inertsolvent having a relatively high boiling point such as aliphatic andaromatic hydrocarbons, e.g., petroleum ether, dimethylbenzene and thelike.

The compounds of formula (I) wherein Q is a1,4-dihydro-2-oxo-3(2H)-quinazolinyl radical and wherein X is aspreviously described but other than >CO, said X being represented by X'and said compounds by the formula (I-d), may also be prepared byacylating an intermediate of formula (IV-e) wherein R⁷ is hydrogen,lower alkyl, aryl or aryllower alkyl and R¹, n and R³ are as previouslydescribed, with a trihalo-acetic or -ethanethioic acid, or an acidhalide thereof, subsequently reacting the thus obtained acylate (IX)with an amine of formula (VIII-b) and cyclizing the thus obtainedSchiff's base (X) in the presence of an appropriate reducing aget, e.g.,sodium borohydride and the like. ##STR13##

The acylation is carried out following art-known acylating procedures.The Schiff's base is prepared by stirring and heating the intermediates(IX) and (VIII-b) together in the presence of a suitable solvent, suchas, for example, an alcohol, e.g., methanol and the like. The reductivecyclization is carried out by stirring the Schiff's base (X) and thereducing agent, e.g., sodium borohydride and the like, together in thepresence of a suitable solvent, e.g., N,N-dimethylformamide and thelike. Sometimes external cooling may be appropriate.

The compounds of formula (I) may also be derived from a compound offormula (XI) wherein P represents a precursor of the correspondingAr-X-radical by converting said P into the desired Ar-X followingmethods known in the art. ##STR14##

For example, the compounds of formula (I) wherein Ar-X-is an optionallysubstituted 2-aminobenzoyl radical, said compounds being represented bythe formula (I-e), may be prepared by the oxidative cleavage of thedouble bond in the corresponding indole-derivative (XII) and subsequenthydrolysis of the thus formed formamide (XIII). Said oxidative cleavagemay be carried out by the reaction of (XII) with an appropriateoxidizing agent, such as, for example, sodium periodate in the presenceof a catalytic amount of osmiumtetroxide in a suitable solvent, e.g.1,4-dioxane and the like. The oxidation may equally well be carried outby bubbling ozonized oxygen through a solution of (XII) in acetic acidand subsequently decomposing the intermediately formed ozonide withwater. The thus obtained (formylamino)phenylcarbonyl intermediate (XIII)is then converted into (I-e) by hydrolysis in acidic medium. In thefollowing reaction-equations R⁸ and R⁹ are each independently selectedfrom the group consisting of hydrogen, halo, lower alkyl, loweralkyloxy, trifluoromethyl and amino. ##STR15##

The compounds of formula (I) wherein X is a CHOH radical, (I-f), maygenerally be prepared starting from the correspondingcarbonyl-derivatives, (I-g), by reducing the carbonyl group of thelatter with an appropriate reducing agent, e.g. sodium borohydride,sodium cyanoborohydride and the like following art-known methodologies.##STR16## When, for example, sodium borohydride is used as a reducingagent the reaction may conveniently be carried out in alkaline aqueousmedium, if desired, in admixture with a water-miscible organic solventsuch as, for example, an alicyclic ether, e.g. tetrahydrofuran,1,4-dioxane and the like; or a lower alkanol, e.g. methanol, propanoland the like.

The compounds of formula (I) wherein X represent a radical>CHOC(O)-R_(a), wherein R_(a) has the previously defined meaning, saidcompounds being represented by the formula (I-h), may be derived fromthe corresponding alcohols (I-f) by acylating the latter with anappropriate acylating agent according to art-known procedures.Appropriate acylating agents which may be used for this purpose includelower alkanoic acids and acyl halides and anhydrides derived therefrom.##STR17##

The compounds of formula (I) wherein X is a methylene radical, (I-j),may be derived from the corresponding carbonyl derivatives (I-g) by thereduction of the carbonyl group of (I-g) to a methylene group, e.g. bythe Clemmensen reduction, using amalgated zinc and hydrochloric acid, orby the Wolff-Kishner reduction, using hydrazine and alkali in ahigh-boiling polar solvent, such as, 1,2-ethanediol and the like.##STR18##

The compounds of formula (I) wherein X represents a di(lower alkyl)ketalor a cyclic lower alkylene ketal, wherein the lower alkylene chain hasfrom 2 to 4 carbon atoms, may be derived from the corresponding carbonylcompounds by subjecting the latter to a ketalization-reaction followingmethodologies generally known in the art. Cyclic lower alkylene ketals,for example, may be prepared following methodologies analogous to thosedescribed in Synthesis, 1974, (I) 23-26.

The compounds of formula (I) wherein X represents a radical of theformula >C═NOH or a radical of the formula >C═N-NH₂ can easily bederived from the corresponding carbonyl compounds by reacting the latterwith respectively hydroxylamine hydrochloride or hydrazine hydrochlorideaccording art-known procedures of preparing oximes and hydrazones.

Certain of the intermediates and starting materials used in theforegoing preparations are known compounds, others may be preparedaccording to art-known methodologies of preparing similar compounds andsome of them are novel and consequently their preparation will bedescribed hereafter.

The intermediates of formula (II) can be prepared by converting thehydroxyl function of the corresponding alcohol (XIV) into a reactiveleaving group, e.g., by reacting the alcohol (XIV) with thionylchloride, sulfuryl chloride, phosphor pentabromide, phosphoryl chloride,methanesulfonyl chloride, 4-methylbenzenesulfonyl chloride and the like.The alcohols (XIV), used as starting materials herein, can be derivedfrom an alcohol (XV) wherein Q' is a precursor of Q following similarprocedures as previously described herein for the preparation of (I-a),(I-b), (I-c) and (I-d) starting from appropriate intermediates offormula (IV).

Alternatively, the intermediates of formula (II) can be derived from analcohol (XV) by converting the hydroxyl function into a reactive leavinggroup and subsequently cyclizing the precursor Q' in the thus obtainedintermediate (XVI) following the previously described procedures. In thefollowing reaction-scheme Q, Q', Alk and W have the previously definedmeanings. ##STR19##

The intermediates of the formula (III) may be derived from anintermediate of formula (XVII) by eliminating the protective group Zfollowing art-known procedures. ##STR20##

Said elimination of Z can be carried out following art-known procedures,depending upon the nature of Z, e.g., by catalytically hydrogenating abenzyl analog of (XVII), in case Z is benzyl, or by hydrolyzing a loweralkyloxycarbonyl analog of formula (XVII) in acidic medium, in case Z islower alkyloxycarbonyl.

The intermediates of formula (XVII) may be prepared following art-knownprocedures. For example, the intermediates of formula (XVII) wheren X isCO, (XVII-a), may be prepared starting from an appropriately substituted4-piperidinone (XVIII) and an appropriate arylmethylcyanide (XIX) asshown in the following reaction-scheme. ##STR21##

The reaction of (XVIII) and (XIX) can be carried out by stirring and, ifdesired, heating the reactants together in a suitable reaction-inertsolvent and in the presence of an appropriate base such as, for example,an alkali metal alkanolate, e.g., sodium methanolate and the like. Thecatalytic hydrogenation of (XX) is desirably conducted in a suitablereaction-inert solvent such as, for example, a lower alkanol, e.g.,methanol and the like, in the presence of an appropriate catalyst, e.g.,palladium-on-charcoal and the like. In order to avoid hydrogenation ofthe nitrile group it may be appropriate to add an appropriatecatalyst-poison, e.g., thiophene and the like. The oxidation of the thusobtained (XXI) can be carried out following art-known oxidativeprocedures, e.g., as described in Journal of Organic Chemistry 40, 267(1975).

The intermediates of formula (XVII-a), wherein R is other than hydroxy,said R being represented by R' and said intermediates by (XVII-a-1), canalso be prepared by the Grignard reaction of an appropriatelysubstituted 4-piperidinyl magnesium halide (XXII) with an appropriatearyl cyanide (XXIII). ##STR22##

Said Grignard-reaction is carried out by stirring and, if desired,heating the reactants together in the presence of a suitablereaction-inert solvent, e.g., 1,1'-oxybisethane, tetrahydrofuran and thelike.

The intermediates of formula (III) wherein X is other than CO, (III-b),can be derived from the corresponding arylcarbonylpiperidines, (III-a),following the same procedures as described hereinbefore for thepreparation of compounds (I) wherein X is other than >C═O, starting from(I-g).

The intermediates of formula (IV) can generally be prepared byN-alkylating a piperidine (III) with an appropriately substitutedreactive ester (XVI) following art-known N-alkylating procedures, aspreviously described herein for the preparation of compounds (I)starting from (II) and (III). ##STR23##

The intermediates of formula (IV-a-1) can also be prepared by reducingthe corresponding nitro-derivatives (XXIV) following art-knownnitro-to-amine reduction reactions as known in the art, e.g., bycatalytically hydrogenating the nitro-derivatives (XXIV) in the presenceof an appropriate catalyst, e.g., platinum-on-charcoal and the like, inthe presence of a suitable reaction-inert solvent, e.g., a lower alkanolsuch as methanol and the like. A catalyst poison, e.g., thiophene andthe like may be appropriate to avoid undesired reductions of otherfunctional groups. ##STR24##

The intermediates of formula (IV-a) can generally be derived from theintermediates (IV-a-1) by N-alkylating the latter with an appropriatereactive ester R³ -W, (XXV), following art-known N-alkylatingprocedures. ##STR25##

The nitro-derivatives (XXIV) may themselves be prepared by N-alkylatingan appropriately substituted 2-nitrobenzamide (XXVI) with an appropriatecompound of the formula (XXVII) wherein W and W' are each a reactiveleaving group, provided that W' has better leaving capacity than W. Thethus obtained (XXVIII) is subsequently reacted with an appropriatelysubstituted piperidine derivative (III). ##STR26##

Both N-alkylations are carried out following art-known procedures aspreviously described herein for the preparation of compounds (I)starting from (II) and (III).

The intermediates of formula (XII) may be prepared by N-alkylating apiperidine (XXIX), wherein R, R⁸ and R⁹ are as previously defined, withan appropriate reactive ester of the formula (II) following standardN-alkylating procedures. ##STR27##

The starting compounds (XXIX) herein are described in Belg. Pat. No.858,101 and can be prepared by condensating benzoyl chloride with anappropriately substituted pyridine (XXX) and an appropriatelysubstituted 1H-indole (XXXI), subsequently reducing the thus obtaineddihydro-pyridine (XXXII), e.g., by catalytically hydrogenating thelatter in the presence of an appropriate catalyst, such as, for example,palladium-on-charcoal and the like, and hydrolyzing the benzoylderivative (XXXIII) in alkaline medium. ##STR28##

The compounds of formula (I), the intermediates of formula (XII) andtheir pharmaceutically active acid addition salts have usefulpharmacological properties. They are very potent serotonin-antagonistsand as such they can be used in the treatment of a variety of diseasesin which serotonin release is of predominant importance.

The potency of the subject compounds as serotonin-antagonists is clearlyevidenced by the results obtained in the following tests wherein theantagonistic activity of the compounds (I) on the effect of serotonin isexamined.

Test 1: Antagonistic Activity on the Effect of Serotonin on the CaudalArtery of the Rat

Caudal arteries from fasted male rats (210-235 g) are used in the test.Two helical strips having a length of 5-6 cm and a width of 2 mm areobtained from each artery and mounted vertically in a 100 ml organ bathcontaining an oxygenated Krebs-Henseleit solution. Submaximalcontractions of the arterial strips are produced by adding single dosesof serotonin (40 ng/ml) to the organ bath for 2 minutes with each timean interval of 10 minutes. The amplitude of the contraction is measuredbefore and 5 minutes after adding the drug. After washing out, theagonist is added again three times in order to see whether thecontraction is restored and normalized. The first column of table 1shows the ED₅₀ -values in ng/ml for a number of compounds of formula (I)in the above test. In this connection the ED₅₀ -values are the minimalconcentrations of the concerned drugs which reduce the amplitude of thecontraction to at least 50% of its normal value.

Test 2: Effects in Gastric Lesion Tests A. Lesions Induced by Compound48/80

Compound 48/80 (a mixture of oligomers obtained by condensation of4-methoxy-N-methylbenzenethanamine and formaldehyde) is a potentreleaser of vasoactive amines from endogenous stores such as, forexample, histamine and serotonin. Rats injected with compound 48/80exhibit consistent changes of blood flow in different vascular beds:cyanosis of the ears and the extremities are prominent within fiveminutes after injection of the compound; the rats die from shock within30 minutes. The shock, followed by dead, can be avoided if the rats arepretreated with a classical H 1 antagonist. However the stimulatoryeffects on gastric secretion are not suppressed so that rats treatedwith compound 48/80 and protected from shock by an H 1 antagonist mayexhibit all signs of intensive gastric gland activity: gross autopsyshows distended stomachs with abnormal contents and rough bright redpatches all over the mucosa, corresponding to areas of disintegratedglands. A number of known serotonin antagonists such as, for example,methysergide, cyproheptadine, cinanserin, mianserin, pipamperone,spiperone, pizotifen and metergoline, prevent completely the cyanosis ofears and extremities as well as the lesions in the glandular area of thestomach and the abnormal gastric distension.

B. Method

Male rats of a Wistar inbred strain, weighing 220-250 g, are starvedovernight, water being available ad libitum. The test compounds areadministered orally as a solution or as a suspension in aqueous medium.A control rat and a "blank" rat receive the test compound. One hourlater5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazole-2-methanolis administered subcutaneously to all rats at the dose of 2.5 mg/kg. Twohours after the oral administration of the test compound the compound48/80 (freshly solved in water at a concentration of 0.25 mg/ml) isinjected intravenously into all rats (dose: 1 mg/kg) except the "blank"rats. Five minutes after the injection the intensity of purple-bluecoloration (cyanosis) of the extremities is scored as 0 (absent),+(moderate) or ++(intense). Four hours after the intravenous injectionof compound 48/80 the rats are decapitated and the stomachs are removed.Subsequently the stomachs are inspected for distension and contents(blood, fluid, food) and thoroughly rinsed. The macroscopic lesions arescored from 0 to + ++, 0 corresponding to complete absence of visiblelesions and the highest score corresponding to reddish rough patchescovering more than half the glandular area.

The second column of table 1 shows for a number of compounds of formula(I) the doses (in mg/kg body weight) at which the distension of thestomach as well as the lesions in the glandular area of the stomach arecompletely absent in 50% of the test rats (ED₅₀ -values).

The third column of table 1 shows for a number of compounds of formula(I) the doses (in mg/kg body weight) at which the cyanosis of ears andextremities is completely absent in 50% of the test rats (ED₅₀ -values).

The compounds listed in table 1 are not given for the purpose oflimiting the invention thereto but only to exemplify the usefulpharmacological activities of all the compounds within the scope offormula (I).

                                      TABLE 1                                     __________________________________________________________________________     ##STR29##                                                                                                            Caudal artery                                                                        G. lesion                                                                             Cyanosis               (R.sup.1).sub.n                                                                    R.sup.3                                                                           Y  Alk     R X       Ar        ng/ml  ED.sub.50 in                                                                          ED.sub.50 in           __________________________________________________________________________                                                           mg/kg                  --   H   O  (CH.sub.2).sub.3                                                                      --                                                                              CO      4-FC.sub.6 H.sub.4                                                                      1.25   2.5     --                     --   H   O  (CH.sub.2).sub.2                                                                      --                                                                              CO      4-FC.sub.6 H.sub.4                                                                      0.7    0.16    0.08                   --   H   O  (CH.sub.2).sub.2                                                                      --                                                                              CO      4-ClC.sub.6 H.sub.4                                                                     2.5    --      --                     --   H   O  (CH.sub.2).sub.2                                                                      --                                                                              CO      4-OCH.sub.3C.sub.6 H.sub.4                                                              2.5    --      --                     --   H   S  (CH.sub.2).sub.3                                                                      --                                                                              CO      4-FC.sub.6 H.sub.4                                                                      2      2.5     0.63                   --   H   S  (CH.sub.2).sub.2                                                                      --                                                                              CO      4-FC.sub.6 H.sub.4                                                                      0.6    0.08    0.04                   7-Cl H   O  (CH.sub.2).sub.2                                                                      --                                                                              CO      4-FC.sub.6 H.sub.4                                                                      2      1.25    1.25                   --   CH.sub.3                                                                          O  (CH.sub.2).sub.2                                                                      --                                                                              CO      4-FC.sub.6 H.sub.4                                                                      0.7    1.25    0.16                   --   H   O  (CH.sub.2).sub.2                                                                      --                                                                              CO      2-NH.sub.2, 4-FC.sub.6 H.sub.3                                                          0.6    1.25    0.16                   7-F  H   O  (CH.sub.2).sub.2                                                                      --                                                                              CO      4-FC.sub.6 H.sub.4                                                                      0.7    1.25    0.16                   7-OCH.sub.3                                                                        H   O  (CH.sub.2).sub.2                                                                      --                                                                              CO      4-FC.sub.6 H.sub.4                                                                      0.7    0.31    0.16                   6-CH.sub.3                                                                         H   O  (CH.sub.2).sub.2                                                                      --                                                                              CO      4-FC.sub.6 H.sub.4                                                                      1.3    2.5     0.63                   --   H   O  (CH.sub.2).sub.2                                                                      --                                                                              CHOH    4-FC.sub.6 H.sub.4                                                                      20     1.25    1.25                   --   H   O  (CH.sub.2).sub.2                                                                      --                                                                               ##STR30##                                                                            4-FC.sub.6 H.sub.4                                                                      11     0.31    0.16                   __________________________________________________________________________     ##STR31##                                                                                                            Caudal artery                                                                        G. lesion                                                                             Cyanosis               (R.sup.1).sub.n                                                                    R.sup.4                                                                           Y  Alk     R X       Ar        ng/ml  ED.sub.50 in                                                                          ED.sub.50 in           __________________________________________________________________________                                                           mg/kg                  --   H   O  (CH.sub.2).sub.2                                                                      --                                                                              CO      4-FC.sub.6 H.sub.4                                                                      0.6    0.31    0.31                   --   H   O  (CH.sub.2).sub.3                                                                      --                                                                              CO      4-FC.sub.6 H.sub.4                                                                      5      2.5     --                     --   CH.sub.3                                                                          O  (CH.sub.2).sub.2                                                                      --                                                                              CO      4-FC.sub.6 H.sub.4                                                                      0.6    0.16    0.16                   __________________________________________________________________________     ##STR32##                                                                                                            Caudal artery                                                                        G. lesion                                                                             Cyanosis               (R.sup.1).sub.n                                                                    R.sup.2                                                                          R.sup.3                                                                         R.sup.4                                                                         Alk       X       Ar        ng/ml  ED.sub.50 in                                                                          ED.sub.50 in           __________________________________________________________________________                                                           mg/kg                  --   H  H H (CH.sub.2).sub.2                                                                        CO      4-FC.sub.6 H.sub.4                                                                      0.7    2.5     1.25                   __________________________________________________________________________     ##STR33##                                                                                                            Caudal artery                                                                        G. lesion                                                                             Cyanosis               (R.sup.1).sub.n                                                                    R.sup.3                                                                             R.sup.4                                                                             R.sup.5                                                                            Alk     Ar        ng/ml  ED.sub.50 in                                                                          ED.sub.50 in           __________________________________________________________________________                                                           mg/kg                  --   H     H     H    (CH.sub.2).sub.2                                                                      4-FC.sub.6 H.sub.4                                                                      5      ≧2.5                                                                           --                     --   H     H     H    (CH.sub.2).sub.3                                                                      4-FC.sub.6 H.sub.4                                                                      10     ≧2.5                                                                           --                     __________________________________________________________________________     ##STR34##                                                                                                            Caudal artery                                                                        G. lesion                                                                             Cyanosis               (R.sup.1).sub.n                                                                    R.sup.6     Alk          Ar        ng/ml  ED.sub.50 in                                                                          ED.sub.50 in           __________________________________________________________________________                                                           mg/kg                  --   C.sub.6 H.sub.5                                                                           (CH.sub.2).sub.2                                                                           4-FC.sub.6 H.sub.4                                                                      0.6    0.08    0.08                   6-Cl C.sub.6 H.sub. 5                                                                          (CH.sub.2).sub.2                                                                           4-FC.sub.6 H.sub.4                                                                      --     0.63    0.63                   __________________________________________________________________________     ##STR35##                                                                                                            Caudal artery                                                                        G. lesion                                                                             Cyanosis               (R.sup.1).sub.n                                                                    R.sup.3 R.sup.4 R.sup.5   Alk      ng/ml  ED.sub.50 in                                                                          ED.sub.50 in           __________________________________________________________________________                                                           mg/kg                  --   H       H       H         (CH.sub.2).sub.2                                                                       0.7    0.31    0.16                   __________________________________________________________________________

The compounds of formula (I) and the intermediates of formula (XII)prevent completely the lesions which are caused by excessive serotoninrelease and they also block the serotonin-induced contractions ofbronchial tissues and of blood vessels, arteries as well as veins, and,consequently, the compounds of the present invention can be used in thetreatment of gastrointestinal ulcus, bronchial spasm, hemorrhoids,varises and the like diseases, all of which are caused by congestion.

In view of their useful anti-congestive properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes. To prepare the pharmaceutical compositions ofthis invention, an effective anti-congestive amount of the particularcompound, in base of acid-addition salt form, as the active ingredientis combined in intimate admixture with a pharmaceutically acceptablecarrier, which carrier may take a wide variety of forms depending on theform of preparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable, preferably,for administration orally, rectally or by parenteral injection. Forexample, in preparing the compositions in oral dosage form, any of theusual pharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. Acid additionsalts of (I), due to their increased water solubility over thecorresponding base form, are obviously more suitable in the preparationof aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Although the amount of the active ingredient to be administered may varywithin rather wide limits depending on the particular circumstances,such as the nature and the severity of the disease, doses of from about0.04 to about 4 mg of active ingredient per kg of body weight, andparticularly from about 0.1 to about 2 mg per kg of body weight,administered once or repeatedly, are in general satisfactory.

The following formulations exemplify typical anti-convulsantpharmaceutical compositions in dosage unit form suitable for systemicadministration to animal and human subjects in accordance with thepresent invention. These examples are given to illustrate and not tolimit the scope of the present invention.

Oral Drops

The following formulation provides 50 liters of an oral-drop solutioncomprising 10 mg of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedioneas the active ingredient (A.I.) per milliliter.

    ______________________________________                                        A.I.                 500      grams                                           2-hydroxypropanoic acid                                                                            0.5      liters                                          sodium saccharin     1750     grams                                           cocoa flavor         2.5      liters                                          purified water       2.5      liters                                          polyethylene glycol q.s. ad                                                                        50       liters                                          ______________________________________                                    

The A.I. is dissolved in the 2-hydroxypropanoic acid and 1.5 liters ofthe polyethylene glycol at 60°-80° C. After cooling to 30°-40° C. thereare added 35 liters of polyethylene glycol and the mixture is stirredwell. Then there is added a solution of the sodium saccharin in 2.5liters of purified water and while stirring there are added the cocoaflavor and polyethylene glycol q.s. ad volume. The resulting solution isfilled into suitable containers.

Oral Solution

The following formulation provides 20 liters of an oral solutioncomprising 20 mg of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedioneas the active ingredient (A.I.) per teaspoonful (5 milliliters).

    ______________________________________                                        A.I.                   20    grams                                            2,3-dihydroxybutanedioic acid                                                                        10    grams                                            sodium saccharin       40    grams                                            1,2,3-propanetriol     12    liters                                           Sorbitol 70% solution  3     liters                                           Methyl 4-hydroxybenzoate                                                                             9     grams                                            Propyl 4-hydroxybenzoate                                                                             1     gram                                             Raspberry essence      2     milliliters                                      Gooseberry essence     2     milliliters                                      Purified water q.s. ad 20 liters.                                             ______________________________________                                    

The methyl and propyl 4-hydroxybenzoates are dissolved in 4 liters ofboiling purified water. In 3 liters of this solution are dissolved firstthe 2,3-dihydroxybutanedioic acid and thereafter the A.I.. The lattersolution is combined with the remaining part of the former solution andthe 1,2,3-propanetriol and the sorbitol solution are added thereto. Thesodium saccharin is dissolved in 0.5 liters of water and the raspberryand gooseberry essences are added. The latter solution is combined withthe former, water is added q.s. ad volume and the resulting solution isfilled in suitable containers.

Capsules

The following formulation provides 1000 capsules comprising each 20 mgof3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedioneas the active ingredient (A.I.).

    ______________________________________                                        A.I.                  20     grams                                            Sodium lauryl sulfate 6      grams                                            Starch                56     grams                                            Lactose               56     grams                                            Colloidal silicon dioxide                                                                           0.8    grams                                            Magnesium stearate    1.2    grams                                            ______________________________________                                    

The composition is prepared by stirring the ingredients vigorouslytogether. The resulting mixture is subsequently filled into suitablehardened gelatine capsules.

Film-coated Tablets

10.000 compressed tablets, each containing as the active ingredient 10mg of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione,are prepared from the following formulation:

    ______________________________________                                        Tablet core:                                                                  A.I.                   100     grams                                          Lactose                570     grams                                          Starch                 200     grams                                          Polyvinylpyrrolidone (Kollidon-K 90)                                                                 10      grams                                          Microcrystalline cellulose                                                    (Avicel)               100     grams                                          Sodium dodecyl sulfate 5       grams                                          Hydrogenated vegetable oil                                                    (Sterotex)             15      grams                                          Coating:                                                                      Methyl cellulose (Methocel 60 HG)                                                                    10      grams                                          Ethyl cellulose (Ethocel 22 cps)                                                                     5       grams                                          1,2,3-propanetriol     2.5     milliliters                                    Polyethylene glycol 6000                                                                             10      grams                                          Concentrated colour suspension                                                                       30      milliliters                                    (Opaspray K-1-2109)                                                           Polyvinylpyrrolidone (Povidone)                                                                      5       grams                                          Magnesium octadecanoate                                                                              2.5     grams                                          ______________________________________                                    

Preparation of Tablet Core

A mixture of the A.I., the lactose and the starch is mixed well andthereafter humidified with a solution of the sodium dodecyl sulfate andthe polyvinylpyrrolidone in about 200 milliliters of water. The wetpowder mixture is sieved, dried and sieved again. Then there is addedthe microcrystalline cellulose and the hydrogenated vegetable oil. Thewhole is mixed well and compressed into tablets.

Coating

To a solution of the methyl cellulose in 75 milliliters of denaturatedethanol there is added a solution of the ethyl cellulose in 150milliliters of dichloromethane. Then there are added 75 milliliters ofdichloromethane and the 1,2,3-propanetriol. The polyethylene glycol ismolten and dissolved in 75 milliliters of dichloromethane. The lattersolution is added to the former and then there are added the magnesiumoctadecanoate, the polyvinylpyrrolidone and the concentrated coloursuspension and the whole is homogenated.

The tablet cores are coated with the thus obtained mixture in a coatingapparatus.

Injectable Solution

The following formulation provides 1 liter of a parenteral solutioncomprising 4 mg of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedioneas the active ingredient per milliliter.

    ______________________________________                                        A.I.                   4      grams                                           Lactic acid            4      grams                                           Propylene glycol       0.05   grams                                           Methyl 4-hydroxybenzoate                                                                             1.8    grams                                           Propyl 4-hydroxybenzoate                                                                             0.2    grams                                           Purified water q.s. ad 1 liter.                                               ______________________________________                                    

The methyl and propyl 4-hydroxybenzoates are dissolved in about 0.5liters of boiling water for injection. After cooling to about 50° C.there are added while stirring the lactic acid, the propylene glycol andthe A.I.. The solution is cooled to room temperature and supplementedwith water for injection q.s. ad volume. The solution is sterilized byfiltration (U.S.P. XVII p. 811) and filled in sterile containers.

Suppositories

100 Suppositories each containing 20 mg of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedioneas the active ingredient are prepared from the following formulations:

    ______________________________________                                        A.I.                   3     grams                                            2,3-Dihydroxybutanedioic acid                                                                        3     grams                                            Polyethylene glycol 400                                                                              25    milliliters                                      Surfactant (Span)      12    grams                                            Triglycerides (Witepsol 555) q.s. ad 300 grams.                               ______________________________________                                    

The A.I. is dissolved in a solution of the 2,3-dihydroxybutanedioic acidin the polyethylene glycol 400. The surfactant and the triglycerides aremolten together. The latter mixture is mixed well with the formersolution. The thus obtained mixture is poured into moulds at atemperature of 37°-38° C. to form the suppositories.

In view of the anti-congestive activity of the subject compounds, it isevident that the present invention provides a method of treatingcongestive diseases of warm-blooded animals by the systemicadministration of an effective anti-congestive amount of a compound offormula (I) or of an intermediate of formula (XII) or a pharmaceuticallyacceptable acid addition salt thereof in admixture with a pharmaceuticalcarrier.

The following examples are intended to illustrate but not to limit thescope of the present invention. Unless otherwise stated all parts hereinare by weight and all temperatures are in the centigrade scale.

(A) Preparation of Intermediates

EXAMPLE I

To 5 parts of magnesium are added 2.18 parts of 1,2-dibromoethane and asmall amount of iodine to initiate the reaction. Then there is addeddropwise a solution of 28 parts of 4-chloro-1-methylpiperidine in 180parts of tetrahydrofuran while the mixture is heated to 70° C. Aftercooling, there is added dropwise a solution of 14 parts of3-methylbenzonitrile in 90 parts of tetrahydrofuran. Upon completion,stirring is continued for 1 hour at reflux temperature. The reactionmixture is cooled and poured onto a solution of 75 parts of ammoniumchloride in water. The product is extracted with 2,2'-oxybispropane. Theextract is washed with water, dried, filtered and evaporated, yielding35 parts of (3-methylphenyl) (1-methyl-4-piperidinyl)methanone as anoily residue.

Following the same procedure and using equivalent amounts of theappropriately substituted benzonitriles and 4-chloro-1-methylpiperidinethere are also prepared:

(4-bromophenyl) (1-methyl-4-piperidinyl)methanone as a residue; and

(2-chlorophenyl) (1-methyl-4-piperidinyl)methanone as an oily residue.

EXAMPLE II

To 7 parts of magnesium is added dropwise a solution of 50 parts of1-bromo-2-methylbenzene in 140 parts of 1,1'-oxybisethane so that themixture is refluxing. The whole is stirred for 15 minutes at reflux. TheGrignard-complex is cooled to 10° C. and there is added dropwise asolution of 36 parts of 1-(phenylmethyl)-4-piperidinecarbonitrile in 70parts of 1,1'-oxybisethane. Upon completion, stirring is continued for 4hours at room temperature. The reaction mixture is decomposed with asolution of 40 parts of ammonium chloride in 400 parts of water. Theorganic phase is separated, dried, filtered and evaporated, yielding 31parts of (2-methylphenyl) [1-(phenylmethyl)-4-piperidinyl]methanone asan oily residue.

EXAMPLE III

To a stirred mixture of 35 parts of (3-methylphenyl)(1-methyl-4-piperidinyl)methanone, 1 part of sodium carbonate and 225parts of dimethylbenzene are added dropwise 22 parts of ethylcarbonochloridate at 20° C. Upon completion, stirring is continued for 6hours at reflux temperature. The reaction mixture is evaporated,yielding 12 parts of ethyl 4-(3-methylbenzoyl)-1-piperidinecarboxylateas an oily residue.

In a similar manner there are also prepared starting from thecorresponding phenyl(1-methyl or 1-phenylmethyl-4-piperidinyl)methanone:

ethyl 4-(4-bromobenzoyl)-1-piperidinecaboxylate as a residue;

ethyl 4-(2-chlorobenzoyl)-1-piperidinecarboxylate as an oily residue;and

ethyl 4-(2-methylbenzoyl)-1-piperidinecarboxylate as an oily residue.

EXAMPLE IV

A mixture of 12 parts of ethyl4-(3-methylbenzoyl)-1-piperidinecarboxylate and 225 parts of ahydrobromic acid solution 48% in water is stirred and refluxed for 3hours. The reaction mixture is evaporated and the residue iscrystallized from 2-propanol, yielding 7.5 parts of (3-methylphenyl)(4-piperidinyl)methanone hydrobromide.

Following the same hydrolysis-procedure there are also prepared:

(4-bromophenyl) (4-piperidinyl)methanone hydrobromide;

(2-chlorophenyl) (4-piperidinyl)methanone hydrobromide; mp. 200° C.; and

(2-methylphenyl) (4-piperidinyl)methanone hydrobromide.

EXAMPLE V

A mixture of 25 parts of 2-chloropropanenitrile, 61 parts of(4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 63 parts ofsodium carbonate and 160 parts of acetonitrile is stirred and refluxed(100° C.) overnight. The reaction mixture is cooled, water is added andthe layers are separated. The aqueous phase is extracted with4-methyl-2-pentanone. The combined organic phases are dried, filteredand evaporated. The residue is purified by column-chromatography oversilica gel using a mixture of trichloromethane, hexane and methanol(50:49:1 by volume) as eluent. The pure fractions are collected and theeluent is evaporated. The solid residue is crystallized from2,2'-oxybispropane. The product is filtered off, and dried yielding 17parts of 4-(4-fluorobenzoyl)-α-methyl-1-piperidineacetonitrile; mp.126.7° C.

A mixture of 32 parts of4-(4-fluorobenzoyl)-α-methyl-1-piperidineacetonitrile and 400 parts ofmethanol, saturated with ammonia is hydrogenated in the Parr-apparatusat 25° C. with 5 parts of Raney-nickel catalyst. After the calculatedamount of hydrogen is taken up, the catalyst is filtered off and thefiltrate is evaporated. The residue is taken up in methylbenzene and thelatter is evaporated again. The residue is dissolved in2,2'-oxybispropane and the solution is filtered till clear. The solventis evaporated, yielding 32 parts (100%) of[1-(2-amino-1-methylethyl)-4-piperidinyl] (4-fluorophenyl)methanone asan oily residue.

EXAMPLE VI

A mixture of 4.5 parts of 1-chloro-3,3-diethoxypropane, 12.15 parts of(4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 10.6 parts ofsodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred andrefluxed overnight. The reaction mixture is cooled, water is added andthe layers are separated. The organic phase is dried, filtered andevaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (95:5 by volume) aseluent. The pure factors are collected and the eluent is evaporated. Theresidue is crystallized from a mixture of methylbenzene and2,2'-oxybispropane, yielding 9 parts (53%) of[1-(3,3-diethoxypropyl)-4-piperidinyl] (4-fluorophenyl)methanone.

EXAMPLE VII

A mixture of 50 parts of 2-amino-3,5-dichlorobenzoic acid and 240 partsof ethanol is saturated with gaseous hydrogen chloride. The whole isstirred and refluxed for 10 hours. The reaction mixture is allowed tocool and the solvent is evaporated. To the solid residue are added waterand sodium hydroxide. The precipitated product is filtered off anddried, yielding 25 parts of ethyl 2-amino-3,5-dichlorobenzoate.

To a stirred mixture of 25 parts of ethyl 2-amino-3,5-dichlorobenzoateand 180 parts of dimethylbenzene are added dropwise 30 parts of ethylcarbonochloridate. Upon completion, stirring is continued for 8 hours atreflux temperature. The reaction mixture is evaporated and the residueis crystallized from petroleumether. The product is filtered off anddried, yielding 30 parts of ethyl3,5-dichloro-2-(ethoxycarbonylamino)benzoate.

EXAMPLE VIII

A mixture of 40 parts of ethyl4-chloro-2-[(ethoxycarbonyl)amino]benzoate and 10 parts of2-aminoethanol is stirred and heated to 160°-170° C. while the formedethanol is distilled off. After stirring for about 30 minutes, themixture is cooled and 2-propanol is added. The solid product is filteredoff and dried, yielding 23 parts (64%) of7-chloro-3-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione.

Following the same cyclization procedure and using equivalent amounts ofthe appropriately substituted 2-[(ethoxycarbonyl)amino]benzoates and2-aminoethanol there are also prepared:

3-(2-hydroxyethyl)-1-methyl-2,4(1H,3H)-quinazolinedione;

6-chloro-3-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione;

6,8-dichloro-3-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione; and

3-(2-hydroxyethyl)-6-methyl-2,4(1H,3H)-quinazolinedione.

EXAMPLE IX

A mixture of 14 parts of6-chloro-3,4-dihydro-3-(2-hydroxyethyl)-4-phenyl-2(1H)-quinazolinone, 5parts of sodium acetate and 200 parts of methanol is hydrogenated atnormal pressure and at room temperature with 2 parts ofpalladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen is taken up, the catalyst is filtered off and the filtrate isevaporated. The residue is stirred in 2,2'-oxybispropane. The solidproduct is filtered off and stirred in 200 parts of water. It isfiltered off again and dried, yielding 11.2 parts (91%) of3,4-dihydro-3-(2-hydroxyethyl)-4-phenyl-2(1H)-quinazolinone; mp. 141° C.

EXAMPLE X

A mixture of 23 parts of7-chloro-3-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione, 32 parts ofthionyl chloride and 150 parts of trichloromethane is stirred andrefluxed for 4 hours. The reaction mixture is cooled. The precipitatedproduct is filtered off, washed with trichloromethane and withpetroleumether, and dried, yielding 22 parts (88%) of7-chloro-3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedione.

In a similar manner there are also prepared:

3-(2-chloroethyl)-1-methyl-2,4(1H,3H)-quinazolinedione;

3-(2-chloroethyl)-3,4-dihydro-4-phenyl-2(1H)-quinazolinone; mp. 179.5°C.

6-chloro-3-(2-chloroethyl)-3,4-dihydro-4-phenyl-2(1H)-quinazolinone;

6-chloro-3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedone;

6,8-dichloro-3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedone; mp. 207° C.;and

3-(2-chloroethyl)-6-methyl-2,4(1H,3H)-quinazolinedione.

EXAMPLE XI

A mixture of 13.6 parts of 2-aminobenzamide, 31.5 parts of1-bromo-3-chloropropane, 21 parts of sodium carbonate and 200 parts ofethanol is stirred and refluxed over week-end. The reaction mixture isfiltered and the filtrate is evaporated. The oily residue is stirred inmethylbenzene. The mixture is filtered till clear and the solvent isevaporated. The oily residue is purified by column-chromatography oversilica gel using a mixture of trichloromethane and methanol (95:5 byvolume) as eluent. The pure fractions are collected and the eluent isevaporated. The solid residue is stirred in 2,2'-oxybispropane. Theproduct is filtered off and dried, yielding 7 parts (33%) of2-[(3-chloropropyl)amino]benzamide; mp. ±100° C.

EXAMPLE XII

A mixture of 10 parts of 2-[(3-chloropropyl)amino]benzamide, 16 parts of2-propanone, 1 part of 4-methylbenzenesulfonic acid and 40 parts ofethanol is stirred and refluxed overnight. The reaction mixture isevaporated and the oily residue is stirred in 2,2'-oxybispropane. Theproduct is filtered off and dried, yielding 10 parts of1-(3-chloropropyl)-2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone.

EXAMPLE XIII

To a stirred and cooled (ice-bath) solution of 27.5 parts of2-bromoethanamine hydrobromide in 200 parts of water is added a solutionof 28.9 parts of 4-methoxy-2-nitrobenzoyl chloride in 63 parts ofbenzene at 5°-10° C. While stirring vigorously, there is added dropwisea solution of 10.8 parts of sodium hydroxide in 250 parts of water at5°-10° C. Upon completion, stirring is continued for 2 hours at thistemperature. The supernatant phase is decanted and the oily residue isstirred in 2-propanol. The product is filtered off and dried, yielding27.5 parts (68%) of N-(2-bromoethyl)-4-methoxy-2-nitrobenzamide; mp.133.8° C.

EXAMPLE XIV

To a stirred and cooled mixture of 25 parts of 2-aminoethanol and 135parts of methylbenzene is added dropwise a solution of 29 parts of4-fluoro-2-nitrobenzoyl chloride in methylbenzene. Upon completion,stirring is continued for 30 minutes at room temperature. Theprecipitated product is filtered off, taken up in water and extractedwith 4-methyl-2-pentanone. The extract is dried, filtered andevaporated, yielding 28 parts (64%) of4-fluoro-N-(2-hydroxyethyl)-2-nitrobenzamide as a residue.

A mixture of 28 parts of 4-fluoro-N-(2-hydroxyethyl)-2-nitrobenzamide,40 parts of thionyl chloride and 150 parts of trichloromethane isstirred and refluxed for 2 hours. After cooling, the precipitatedproduct is filtered off and dried, yielding 24.5 parts (83%) ofN-(2-chloroethyl)-4-fluoro-2-nitrobenzamide.

EXAMPLE XV

A mixture of 14.4 parts of N-(3-bromopropyl)-2-nitrobenzamide, 12.2parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 16parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone isstirred and refluxed for 3 hours using a water-separator. The reactionmixture is cooled, water is added and the layers are separated. Theorganic phase is dried, filtered and evaporated. The oily residue ispurified by column-chromatography over silica gel using a mixture oftrichloromethane and methanol (90:10 by volume) as eluent. The purefractions are collected and the eluent is evaporated, yielding 18 parts(87%) ofN-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2-nitrobenzamide as anoily residue.

Following the same procedure and using equivalent amounts of(4-fluorophenyl) (4-piperidinyl)methanone hydrochloride and anappropriately substituted 2-nitrobenzamide there are also prepared:

N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-nitrobenzamide; mp.150° C.;

4-fluoro-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-nitrobenzamide;mp. 163.5° C.; and

N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-4-methoxy-2-nitrobenzamide;mp. ±134° C.

EXAMPLE XVI

To 1 part of a solution of 2 parts of thophene in 40 parts of ethanolare added 18 parts ofN-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2-nitrobenzamide and 200parts of methanol. The whole is hydrogenated at normal pressure and atroom temperature with 2 parts of platinum-on-charcoal catalyst 5%. Afterthe calculated amount of hydrogen is taken up, the catalyst is filteredoff and the filtrate is evaporated. The oily residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (90:10 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The oily residueis crystallized from 2-propanol. The product is filtered off and dried,yielding 7.5 parts (45%) of2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide; mp.113.2° C. The mother liquor is evaporated, yielding a second fraction of6 parts (36%) of2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide as anoily residue.

Following the same hydrogenating procedure there are also prepared:

2-amino-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide; mp142.5° C.;

2-amino-4-fluoro-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide;mp. 124.1° C.; and

2-amino-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-4-methoxybenzamide;mp. 168.1° C.

EXAMPLE XVII

A mixture of 7.2 parts of 2-[(4-chloro-1-oxobutyl)amino]benzamide, 7.3parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 10.1parts of N,N-diethylethanamine and 120 parts of acetonitrile is stirredand refluxed for 24 hours. The reaction mixture is evaporated and wateris added to the residue. The oily product is extracted withtrichloromethane. The extract is dried, filtered and evaporated,yielding 10 parts (81%) ofN-[2-(aminocarbonyl)phenyl]-4-(4-fluorobenzoyl)-1-piperidinebutanamideas a residue.

EXAMPLE XVIII

A. To a stirred mixture of 250 parts of pyridine and 39 parts of6-fluoro-1H-indole are added dropwise 42 parts of benzoyl chloride at22° C. Upon completion, stirring is continued for 2 hours at roomtemperature. The reaction mixture is diluted with water and ahydrochloric acid solution 2 N is added. The product is extracted twicewith 350 parts of 1,1'-oxybisethane. The combined extracts are dried,filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions are collected and the eluent is evaporated, yielding 95 partsof 1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-1,4-dihydropyridine as an oilyresidue.

B. A mixture of 95 parts of1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-1,4-dihydropyridine and 540 partsof N,N-dimethylacetamide is hydrogenated in the Parr-apparatus with 5parts of palladium-on-charcoal catalyst 10%. After the calculated amountof hydrogen is taken up, the catalyst is filtered off over Hyflo and thefiltrate is poured onto water while stirring: an oil is precipitated.The supernatant aqueous phase is decanted and the residual oil is washedwith water. The oily product is extracted with trichloromethane. Theextract is dried, filtered and evaporated. The residue is washedsuccessively with a mixture of petroleumether and 2,2'-oxybispropane,with a hydrochloric acid solution 2 N and with water, and dissolved intrichloromethane. The latter is washed with a sodium hydroxide solution1 N and with water, dried, filtered and evaporated. The residue isheated in a small amount of N,N-dimethylacetamide at 80° C. and themixture is allowed to stand over week-end. The solid product is filteredoff, washed with a mixture of water and ethanol, and dried in vacuo at80° C., yielding 25 parts of1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-piperidine; mp. 220° C.

C. A mixture of 24 parts of1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-piperidine, 70 parts of potassiumhydroxide, 495 parts of 1,2-ethanediol and 80 parts of water is stirredand refluxed for 6 hours. The reaction mixture is cooled and 500 partsof water are added while stirring. The precipitated product is filteredoff, washed with water and petroleumether and dried in vacuo at 80° C.,yielding 16 parts of 6-fluoro-3-(4-piperidinyl)-1H-indole; mp. 224° C.

D. A mixture of 7.5 parts of3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedione, 6.8 parts of6-fluoro-3-(4-piperidinyl)-1H-indole, 10 parts of sodium carbonate, 0.1parts of potassium iodide and 240 parts of 4-methyl-2-pentanone isstirred and refluxed overnight. Water is added and the layers areseparated. The aqueous phase is set aside. The organic phase is dried,filtered and evaporated. The solid residue is boiled in 2-propanol. Theproduct is filtered off and dried, yielding a first fraction of 4 partsof3-[2-[4-(6-fluoro-1H-indol-3-yl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione.From the aqueous phase (see above), a solid product is filtered off andboiled in 2-propanol. The product is filtered off and dried, yielding asecond fraction of 3 parts of3-[2-[4-(6-fluoro-1H-indol-3-yl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione;mp. 300.6° C.

E. Ozonised oxygen is bubbled through a stirred mixture of 6 parts of3-[2-[4-(6-fluoro-1H-indol-3-yl)-1-piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedioneand 100 parts of acetic acid till a clear solution is obtained. Thenthere are added 200 parts of crushed ice and 100 parts of water and thewhole is alkalized with a sodium hydroxide solution. The product isextracted with trichloromethane and a small amount of ethanol. Theextract is dried, filtered and evaporated, yielding 2.3 parts ofN-[2-[1-[2-(1,4-dihydro-2,4-dioxo-3(2H)-quinazolinyl)ethyl]-4-piperidinylcarbonyl]-5-fluorophenyl]formamideas a residue.

EXAMPLE XIX

A mixture of 13.5 parts of 1-(2-aminophenyl)ethanone, 12.1 parts ofN,N-diethylethanamine and 72 parts of benzenes are stirred and cooled at5°-10° C. Then there is added dropwise a solution of 18.2 parts oftrichloroacetyl chloride in 36 parts of benzene while still cooling at1°-10° C. Upon completion, stirring at that temperature is continued for30 minutes. The reaction mixture is filtered, the filter-cake is washedwith benzene and the filtrate is evaporated. The solid residue is boiledin methanol. After cooling, the product is filtered off and dried,yielding 19 parts (68%) of N-(2-acetylphenyl)-2,2,2-trichloroacetamide;mp. 112.7° C.

A mixture of 60 parts of N-(2-acetylphenyl)-2,2,2-trichloroacetamide, 14parts of 2-aminoethanol and 200 parts of ethanol is stirred first for5.50 hours at reflux and further overnight while the temperature isallowed to cool to room temperature. The formed precipitate is filteredoff. The product is washed with 2,2'-oxybispropane and dried in vacuo,yielding 40 parts (59%) of2,2,2-trichloro-N-[2-[1-[(2-hydroxyethyl)imino]ethyl]phenyl]acetamide;mp. 182° C.

To 135 parts of N,N-dimethylforamide are added first 16.2 parts of2,2,2-trichloro-N-[2-[1-[(2-hydroxyethyl)imino]ethyl]phenyl]acetamideand then portionwise 5.7 parts of sodium borohydride while stirring:exothermic reaction. Upon completion, stirring is continued overnight atroom temperature. The reaction mixture is poured onto water and theproduct is extracted with trichloromethane. The extract is dried,filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (90:10 by volume) as eluent. The purefractions are collected and the eluent is evaporated, yielding 8.5 partsof 3,4-dihydro-3-(2-hydroxyethyl)-4-methyl-2(1H)-quinazolinone as asolid residue.

A mixture of 8 parts of3,4-dihydro-3-(2-hydroxyethyl)-4-methyl-2(1H)-quinazolinone, 8 parts ofthionyl chloride and 90 parts of trichloromethane is stirred andrefluxed for 1.50 hours. The reaction mixture is evaporated. The residueis purified by column-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue isstirred in 2,2'-oxybispropane. The product is filtered off and dried,yielding 6.6 parts of3-(2-chloroethyl)-3,4-dihydro-4-methyl-2(1H)-quinazolinone; mp. 126.4°C.

EXAMPLE XX

To a stirred mixture of 10 parts of methyl2-[(2-hydroxyethyl)amino]benzoate and 100 parts of acetic acid is addeddropwise a solution of 4.5 parts of potassium cyanate in 25 parts ofwater. Upon completion, stirring at room temperature is continuedovernight. The reaction mixture is evaporated. The solid residue isstirred with water. The product is filtered off, washed with water andethanol, and dried, yielding 5 parts (48%) of1-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione; mp. 273.6° C.

A mixture of 3.6 parts of 1-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedioneand 40 parts of thionyl chloride is stirred and refluxed overnight. Thereaction mixture is allowed to cool to room temperature. Theprecipitated product is filtered off, washed with 2,2'-oxybispropane anddried, yielding 3.4 parts (86%) of1-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione; mp. 215.3° C.

Following the same procedure and using equivalent amounts of theappropriate starting materials there are also prepared:

1-(3-hydroxypropyl)-2,4(1H,3H)-quinazolinedione; mp. 240° C.; and

1-(3-chloropropyl)-2,4(1H,3H)-quinazolinedione; mp. 187.1° C.

EXAMPLE XXI

To a stirred mixture of 18 parts of 2-phenyl-4(3H)-quinazolinone and 225parts of N,N-dimethylformamide are added portionwise at room temperature3.2 parts of sodium hydride dispersion 60% (exothermic reaction: thetemperature rises to 34° C.). After the addition is complete, the wholeis stirred for 10 minutes whereafter 12.4 parts of 2-bromoethanol areadded dropwise (slightly exothermic). Upon completion, stirring iscontinued first for one hour at room temperature, then for 2 hours at80° C. and further overnight at room temperature. The reaction mixtureis cooled, poured onto water and the solid product is sucked off. It iswashed with water and 2,2'-oxybispropane and dried in vacuo at 60° C.,yielding 15 parts of 3-(2-hydroxyethyl)-2-phenyl-4(3H)-quinazolinone.

To a stirred mixture of 15 parts of3-(2-hydroxyethyl)-2-phenyl-4(3H)-quinazolineone and 375 parts oftrichloromethane are added dropwise 24 parts of thionyl chloride at roomtemperature. Upon completion, stirring is continued for 2 hours atreflux. The reaction mixture is evaporated. Water is added to theresidue and the whole is neutralized with a sodium hydrogen carbonatesolution. The product is extracted with trichloromethane. The extract iswashed with water, dried, filtered and evaporated. The residue iscrystallized from a mixture of 2,2'-oxybispropane and petroleumether.The product is filtered off and dried, yielding 11.6 parts of3-(2-chloroethyl)-2-phenyl-4(3H)-quinazolinone.

A mixture of 5.5 parts of3-(2-chloroethyl)-2-phenyl-4(3H)-quinazolinone, 3.2 parts of3-(4-piperidinyl)-1H-indole, 7 parts of sodium carbonate, 0.1 parts ofpotassium iodide and 200 parts of 4-methyl-2-pentanone is stirred andrefluxed for 22 hours. The reaction mixture is filtered over Hyflo andthe filtrate is evaporated. The residue is purified bycolumn-chromatography over silic gel using a mixture of trichloromethaneand methanol (92:8 by volume) as eluent. The pure fractions arecollected and the eluent is evaporated. The residue is crystallized froma mixture of ethanol and 1,1'-oxybisethane, yielding 5 parts of3-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-phenyl-4(3H)-quinazolinone;mp. 191.3° C.

EXAMPLE XXII

To a stirred mixture of 80 parts of sodium methoxide and 160 parts ofmethanol are added successively 50 parts of 2-thiopheneacetonitrile andthen dropwise 66 parts of 1-(phenylmethyl)-4-piperidinone. Uponcompletion, the whole is heated to reflux and stirring at refluxtemperature is continued for one hour. The reaction mixture is cooledand evaporated. The residue is distilled in a moleculardistillation-apparatus, yielding about 70 parts ofα-[1-(phenylmethyl)-4-piperidinylidene]-2-thiopheneacetonitrile as aresidue.

A mixture of 70 parts ofα-[1-(phenylmethyl)-4-piperidinylidene]-2-thiopheneacetonitrile in 800parts of methanol is hydrogenated at normal pressure and at roomtemperature with 10 parts of palladium-on-charcoal catalyst 10%. Uponthe calculated amount of hydrogen is taken up, the catalyst is filteredoff and the filtrate is evaporated, yielding 70 parts of1-(phenylmethyl)-α-(2-thienyl)-4-piperidineacetonitrile as a residue.

To a stirred mixture of 29.6 parts of1-(phenylmethyl)-α-(2-thienyl)-4-piperidineacetonitrile in 100 parts ofdimethyl sulfoxide are added portionwise 4 parts of sodium hydridedispersion 60%. Upon completion, stirring is continued overnight. Thereaction mixture is poured onto water. The precipitated product issucked off and extracted with trichloromethane. The extract is dried,filtered and evaporated. The residue is crystallized from2,2'-oxybispropane, yielding 10 parts (35%) of[1-(phenylmethyl)-4-piperidinyl] (2-thienyl) methanone; mp. 100.5° C.

To a stirred mixture of 15 parts of [1-(phenylmethyl)-4-piperidinyl](2-thienyl)methanone in 120 parts of benzene are added dropwise 8 partsof ethyl carbonochloridate. Upon completion, the whole is heated toreflux and stirred for 6 hours at reflux temperature. The reactionmixture is cooled, filtered and evaporated, yielding 13 parts of ethyl4-(2-thienylcarbonyl)-1-piperidinecarboxylate as a residue.

A mixture of 20 parts of ethyl4-(2-thienylcarbonyl)-1-piperidinecarboxylate and 120 parts ofhydrobromic acid solution 48% in water is stirred and refluxed for 2hours. The reaction mixture is cooled and the precipitated product isfiltered off. It is washed with 2-propanol and dried, yielding 17 parts(85%) of (4-piperidinyl) (2-thienyl)methanone hydrobromide.

(b) Preparation of Final Compounds EXAMPLE XXIII

A mixture of 4.5 parts of 3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedione,4.9 parts of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride, 8parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone isstirred and refluxed overnight. The reaction mixture is cooled and wateris added. The precipitated product is filtered off and crystallized from4-methyl-2-pentanone, yielding, after drying, 2,2 parts (27%) of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedione;mp. 227°-235° C.

Following the same procedure and using equivalent amounts of theappropriate starting materials there are also prepared:

    __________________________________________________________________________     ##STR36##                                                                                                       Melting Point                              (R.sup.1).sub.n                                                                   R.sup.3                                                                          Alk R   X    Ar      Base or Salt                                                                         in °C.                              __________________________________________________________________________    --  H  (CH.sub.2).sub.3                                                                  H   CO   4-FC.sub.6 H.sub.4                                                                    --     187.2                                      --  H  (CH.sub.2).sub.2                                                                  H   CO   4-ClC.sub.6 H.sub.4                                                                   --     259                                        --  H  (CH.sub.2).sub.2                                                                  H   CO   4-OCH.sub.3C.sub.6 H.sub.4                                                            --     236.5                                      --  H  (CH.sub.2).sub.2                                                                  H   CO   4-CH.sub.3C.sub.6 H.sub.4                                                             --     211.7                                      7-Cl                                                                              H  (CH.sub.2).sub.2                                                                  H   CO   4-FC.sub.6 H.sub.4                                                                    --     235.2                                      --  CH.sub.3                                                                         (CH.sub.2).sub.2                                                                  H   CO   4-FC.sub.6 H.sub.4                                                                    HCl    248.1                                      --  H  (CH.sub.2).sub.2                                                                  H   CO   3-CF.sub.3C.sub.6 H.sub.4                                                             --     182.6-184.6                                --  H  (CH.sub.2).sub.2                                                                  H   CO   3-CH.sub.3C.sub.6 H.sub.4                                                             --     171                                        --  H  (CH.sub.2).sub.2                                                                  H   CO   4-BrC.sub.6 H.sub.4                                                                   --     251.5                                      6,8-Cl.sub.2                                                                      H  (CH.sub.2).sub.2                                                                  H   CO   4-FC.sub.6 H.sub.4                                                                    --     211                                        --  H  (CH.sub.2).sub.2                                                                  H   CO   2-ClC.sub.6 H.sub.4                                                                   --     162.5                                      --  H  (CH.sub.2).sub.2                                                                  H                                                                                  ##STR37##                                                                         4-FC.sub.6 H.sub.4                                                                    --     204.5                                      --  H  (CH.sub.2).sub.2                                                                  H   CH.sub.2                                                                           4-FC.sub.6 H.sub.4                                                                    --     193.4                                      --  H  (CH.sub.2).sub.2                                                                  4-OH                                                                              CO   4-FC.sub.6 H.sub.4                                                                    --     255.2                                      6-Cl                                                                              H  (CH.sub.2).sub.2                                                                  H   CO   4-FC.sub.6 H.sub.4                                                                    --     222.2-223                                  6-CH.sub.3                                                                        H  (CH.sub.2).sub.2                                                                  H   CO   4-FC.sub.6 H.sub.4                                                                    --     205.5                                      --  H  (CH.sub.2).sub.2                                                                  H   CO   C.sub.6 H.sub.5                                                                       --     214.5                                      --  H  (CH.sub.2).sub.2                                                                  H   CO   2-CH.sub.3C.sub.6 H.sub.4                                                             --     193.8                                      --  H  (CH.sub.2).sub.2                                                                  H   CO   2-thienyl                                                                             --     266.9                                      __________________________________________________________________________

EXAMPLE XXIV

A mixture of 6 parts of3-(2-chloroethyl)-1-phenyl-2,4(1H,3H)-quinazolinedione, 8.3 parts of(4-fluorophenyl) (4-piperidinyl)methanone and 48 parts of ethanol isstirred and refluxed. N,N-dimethylformamide is added at refluxtemperature till all solid enters solution. Stirring is continuedovernight at reflux. The reaction mixture is evaporated. The residue ispurified twice by column-chromatography over silica gel using first amixture of trichloromethane and methanol (95:5 by volume) and then amixture of trichloromethane and methanol (98:2 by volume) as eluent. Thepure fractions are collected and the eluent is evaporated. The residueis crystallized from 2-propanol, yielding 2.2 parts (23%) of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-1-phenyl-2,4(1H,3H)-quinazolinedione;mp. 166.1° C.

EXAMPLE XXV

A mixture of 5.8 parts of6-chloro-3-(2-chloroethyl)-3,4-dihydro-4-phenyl-2(1H)-quinazolinone, 7.4parts of (4-fluorophenyl) (4-piperidinyl)methanone and 56 parts ofethanol is stirred and refluxed overnight. The reaction mixture isevaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (95:5 by volume) aseluent. The pure fractions are collected and the eluent is evaporated.The oily residue solidifies on triturating in 2,2'-oxybispropane. Theproduct is filtered off and dried, yielding 5 parts (57%) of6-chloro-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-3,4-dihydro-4-phenyl-2(1H)-quinazolinone;mp. 196° C.

In a similar manner there are also prepared:

3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-3,4-dihydro-4-phenyl-2(1H)-quinazolinone;mp. 173.3° C.; and

3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-3,4-dihydro-4-methyl-2(1H)-quinazolinone;mp. 172° C.

EXAMPLE XXVI

A mixture of 3.6 parts of1-(3-chloropropyl)-2,4(1H,3H)-quinazolinedione, 3.02 parts of(4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 3.7 parts ofsodium carbonate, 0.1 parts of potassium iodide and 120 parts of4-methyl-2-pentanone is stirred and refluxed overnight using awater-separator. The reaction mixture is cooled, water is added and thelayers are separated. The organic phase is dried, filtered andconcentrated to a small volume. After cooling the concentrate, theprecipitated product is filtered off and crystallized from 2-propanol,yielding 1.3 parts (18.5%) of1-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2,4(1H,3H)-quinazolinedione;mp. 192.9° C.

Following the same procedure and starting from1-(2-chloroethyl)-2,4(1H,3H)-quinazolinedione there is also prepared:

1-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione;mp. 219.7° C.

EXAMPLE XXVII

A mixture of 5.6 parts of1-(3-chloropropyl)-2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone, 4.9parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 10parts of sodium carbonate, 0.1 parts of potassium iodide and 200 partsof 4-methyl-2-pentanone is stirred and refluxed overnight withwater-separator. The reaction mixture is cooled, water is added and thelayers are separated. The 4-methyl-2-pentanone phase is dried, filteredand evaporated. The solid residue is purified by column-chromatographyover silica gel using a mixture of trichloromethane and methanol (95:5by volume) as eluent. The pure fractions are collected and the eluent isevaporated. The solid residue is stirred in 2,2'-oxybispropane. Theproduct is filtered off and dried, yielding 6.6 parts (78%) of1-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone;mp. 185.7° C.

EXAMPLE XXVIII

A mixture of 5.5 parts of3-(2-chloroethyl)-2-phenyl-4(3H)-quinazolinone, 4 parts of(4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 7 parts ofsodium carbonate, 0.1 parts of potassium iodide and 200 parts of4-methyl-2-pentanone is stirred and refluxed for 24 hours using awater-separator. The reaction mixture is filtered while hot. Thefiltrate is evaporated. The residue is purified by column-chromatographyover silica gel using a mixture of trichloromethane and methanol (95:5by volume) as eluent. The pure fractions are collected and the eluent isevaporated. The residue is crystallized from a mixture of ethanol and1,1'-oxybisethane. The product is filtered off and dried, yielding 5parts (69%) of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-phenyl-4(3H)-quinazolinone;mp. 143.8° C.

EXAMPLE XXIX

A mixture of 10 parts ofN-[2-(aminocarbonyl)phenyl]-4-(4-fluorobenzoyl)-1-piperidinebutanamide,60 parts of sodium hydroxide solution 2 N and 80 parts of ethanol isstirred and refluxed for 1.50 hours. The reaction mixture is evaporatedand water is added to the residue. The oily product is dissolved intrichloromethane. The solution is dried, filtered and evaporated. Theresidue is crystallized twice from 4-methyl-2-pentanone. The product isfiltered off and dried, yielding 1 part (10.5%) of2-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-4(3H)-quinazolinone; mp.184° C.

EXAMPLE XXX

A mixture of 7 parts of2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide, 12parts of formic acid and 135 parts of methylbenzene is stirred andrefluxed for 1 hour. Stirring at reflux is continued for 1 hour using awater-separator. The solvent is evaporated. The oily residue is purifiedby column-chromatography over silica gel using a mixture oftrichloromethane and methanol (90:10 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue isconverted into the (E)-2-butenedioate salt in 2-propanol. The salt isfiltered off and dried, yielding 5 parts (54%) of3-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-4(3H)-quinazolinone(E)-2-butenedioate (1:1); mp. 201.1° C.

Following the same procedure and starting from2-amino-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide there isalso prepared:

3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-4(3H)-quinazolinone; mp.139.2° C.

EXAMPLE XXXI

A mixture of 6.5 parts of2-amino-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide, 0.5parts of paraformaldehyde, 3 drops of sodium hydroxide solution 50%, 80parts of ethanol and 10 parts of water is stirred and refluxedovernight. The reaction mixture is allowed to cool to room temperaturewhile stirring. The precipitated product if filtered off, washed withethanol and crystallized from 200 parts of ethanol, yielding 3.3 parts(50%) of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-4(1H)-quinazolinone;mp. 203.4° C.

Following the same procedure and starting from2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide thereis also prepared:

3-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2,3-dihydro-4-(1H)-quinazolinone(E)-2-butenedioate (1:1); mp. 188.2° C.

EXAMPLE XXXII

A mixture of 6 parts of2-amino-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide, 10parts of acetic acid anhydride and 108 parts of methylbenzene is stirredand refluxed overnight. The reaction mixture is evaporated and water isadded to the oily residue. The whole is alkalized with a dilute sodiumhydroxide solution and extracted with trichloromethane. The extract isdried, filtered and evaporated. The oily residue is crystallized from amixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product isfiltered off and recrystallized from 2-propanol, yielding 4.4 parts(69%) of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4(3H)-quinazolinone;mp. 164.9° C.

EXAMPLE XXXIII

A mixture of 9 parts of 2-aminobenzenecarboxamide, 12 parts ofconcentrated hydrochloric acid and 120 parts of absolute ethanol isstirred and refluxed for 2 hours. Then there are added 3.6 parts of[1-(3,3-diethoxypropyl)-4-piperidinyl](4-fluorophenyl) methanone andstirring at reflux is continued overnight. The reaction mixture isevaporated and the residue is stirred with water. The whole is alkalizedwith ammonia and the product is extracted with trichloromethane. Theextract is dried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized twice from 4-methyl-2-pentanone, yielding 1.9 parts (19%)of2-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-4(1H)-quinazolinone;mp. 153.4° C.

EXAMPLE XXXIV

A mixture of 6.7 parts of methyl 2-isothiocyanatobenzoate, 8 parts of[1-(2-amino-1-methylethyl)-4-piperidinyl](4-fluorophenyl)methanone and108 parts of tetrahydrofuran is stirred overnight at room temperature.The reaction mixture is evaporated. The residue is purified twice bycolumn-chromatography over silica gel using first a mixture oftrichloromethane and methanol (90:10 by volume) and then a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized twice from 2-propanol, yielding 1.6 parts (13%) of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone;mp. 160.6° C.

EXAMPLE XXXV

A mixture of 2.2 parts of2-amino-4-fluoro-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide,1.2 parts of 1,1'-bis[1H-imidazol-1-yl]methanone and 45 parts oftetrahydrofuran is stirred and refluxed for 3 hours. The reactionmixture is cooled and the solvent is evaporated. The residue is boiledin 4-methyl-2-pentanone. The solid product is filtered off andcrystallized from N,N-dimethylformamide, yielding 0.8 parts (30%) of7-fluoro-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione;mp. 248° C.

In a similar manner there is also prepared:

3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-7-methoxy-2,4(1H,3H)-quinazolinedione;mp. 245.4° C.

EXAMPLE XXXVI

To a stirred solution of 6.5 parts of2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide in 63parts of tetrahydrofuran are added 3 parts of1,1'-bis[1H-imidazol-1-yl]methanethione at room temperature. Stirring iscontinued for 1 hour at room temperature. The reaction mixture isfiltered till clear and the solvent is evaporated. The oily residue isstirred in a mixture of water and 2,2'-oxybispropane. The precipitatedproduct is filtered off and crystallized from a mixture ofN,N-dimethylformamide, water and a small amount of ethanol, yielding 5.6parts (78%) of3-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone;mp. 200.2° C.

In a similar manner there is also prepared:

3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone;mp. 225.5° C.

EXAMPLE XXXVII

A mixture of 2.3 parts ofN-[2-[1-[2-(1,4-dihydro-2,4-dioxo-3(2H)-quinazolinyl)ethyl]-4-piperidinylcarbonyl]-5-fluorophenyl]formamide,33 parts of concentrated sulfuric acid and 144 parts of ethanol isstirred and refluxed for 1 hour. The reaction mixture is poured ontocrushed ice and alkalized with a dilute sodium hydroxide solution. Theprecipitated product is filtered off and crystallized from4-methyl-2-pentanone, yielding 0.4 parts of3-[2-[4-(2-amino-4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione;mp. 269.5° C.

EXAMPLE XXXVIII

To a stirred mixture of 2.6 parts of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedioneand 120 parts of methanol are added portionwise 2 parts of sodiumborohydride. Upon completion, stirring is continued overnight at roomtemperature. Water is added and the whole is evaporated. The residue isstirred in water. The solid product is filtered off and crystallizedfrom 2-propanone, yielding 1.2 parts of3-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione;mp. 212.8° C.

EXAMPLE XXXIX

A mixture of 5 parts of 3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedione, 6parts of α-(4-fluorophenyl)-4-piperidinemethanol acetate (ester)hydrochloride, 8 parts of sodium carbonate and 280 parts of4-methyl-2-pentanone is stirred and refluxed overnight. The reactionmixture is filtered and the filtrate is evaporated. The oily residue ispurified by column-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from 4-methyl-2-pentanone, yielding 2.3 parts of1-[2-(1,4-dihydro-2,4-dioxo-3(2H)-quinazolinyl)ethyl]-α-(4-fluorophenyl)-4-piperidinemethanolacetate (ester); mp. 185.2° C.

EXAMPLE XL

Following the procedure described in Example XXV and using equivalentamounts of the appropriate starting materials there is also prepared:

3,4-dihydro-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2(1H)-quinazolinone;mp. 182.1° C.

EXAMPLE XLI

Following the procedure described in Example XXIII and using equivalentamounts of the appropriate starting materials there is also prepared:

3-[2-[4-(3-pyridinylcarbonyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione.

EXAMPLE XLII

Following the procedure described in Example XVIII-D and usingequivalent amounts of the appropriate starting materials there is alsoprepared:

3-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione;mp. 291.2° C.

What is claimed is:
 1. A chemical compound selected from the groupconsisting of a quinazoline compound having the formula ##STR38## andthe pharmaceutically acceptable acid addition salts thereof, wherein; Aris a number selected from the group consisting of aryl, thienyl, andpyridinyl radicals;X is a member selected from the group consisting of##STR39## wherein said q is the integer 2 or 3; R is a member selectedfrom the group consisting of hydrogen, hydroxy and lower alkyl; Alk isan alkylene chain having from 1 to 4 carbon atoms; and Q is aquinazolinyl radical, the 1-, 2-, 3- or 4-position of which is connectedwith the alkylene side chain, said quinazolinyl radical bearing in oneor both of its 2- and 4-positions a oxo or thioxo group, wherein thebenzene ring of said quinazolinyl radical is optionally substituted with1 to 3 substituents each independently selected from the groupconsisting of halo, lower alkyl, lower alkyloxy, trifluoromethyl, nitroand cyano, and wherein the pyrimidino ring of said quinazolinyl radicalmay be partly or fully saturated, said pyrimidino ring being optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of lower alkyl, aryl, aryl(lower alkyl), thienyl,pyridinyl, thienyl(loweralkyl), and pyridinyl (loweralkyl); wherein saidaryl as used in the definition of said Ar and of said Q is a memberselected from the group consisting of phenyl substituted with from 1 to2 substituents each independently selected from the group consisting ofhalo, lower alkyl, lower alkyloxy, trifluoromethyl and amino.
 2. Achemical compound according to claim 1 wherein X is CO.
 3. A chemicalcompound according to claim 2 wherein Alk is an 1,2-ethanediyl radical.4. A chemical compound selected from the group consisting of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedioneand the pharmaceutically acceptable acid addition salts thereof.
 5. Achemical compound according to claim 1 wherein Ar is an aryl radical, Xis >C═O, Alk is an alkylene chain having 2 or 3 carbon atoms; and Q isconnected to the alkylene side chain by the 2- or 3-position.
 6. Ananti-congestive composition comprising an inert carrier and as an activeingredient an effective anticongestive amount of a chemical compoundselected from the group consisting of a quinazoline compound having theformula ##STR40## and the pharmaceutically acceptable acid additionsalts thereof, wherein: Ar is a member selected from the groupconsisting of aryl, thienyl, and pyridinyl radicals;X is a memberselected from the group consisting of ##STR41## wherein said q is theinteger 2 or 3; R is a member selected from the group consisting ofhydrogen, hydroxy and lower alkyl; Alk is an alkylene chain having from1 to 4 carbon atoms; and Q is a quinazolinyl radical, the 1-, 2-, 3- or4-position ofwhich is connected with the alkylene side chain, saidquinazolinyl radical bearing in one or both of its 2- and 4-positions aoxo or thioxo group, wherein the benzene ring of said quinazolinylradical is optionally substituted with 1 to 3 substituents eachindependently selected from the group consisting of halo, lower alkyl,lower alkyloxy, trifluoromethyl, nitro and cyano, and wherein thepyrimidino ring of said quinazolinyl radical may be partly or fullysaturated, said pyrimidino ring being optionally substituted with 1 to 3substituents independently selected from the group consisting of loweralkyl, aryl, aryl(lower alkyl), thienyl, pyridinyl, thienyl(loweralkyl), and pyridinyl (loweralkyl); wherein said aryl as used inthe definition of said Ar and of said Q is a member selected from thegroup consisting of phenyl substituted with from 1 to 2 substituentseach independently selected from the group consisting of halo, loweralkyl, lower alkyloxy, trifluoromethyl and amino.
 7. An anti-congestivecomposition according to claim 6 wherein X is CO.
 8. An anti-congestivecomposition according to claim 7 wherein Alk is an 1,2-ethanediylradical.
 9. An anti-congestive composition comprising an inert carrierand as an active ingredient an effective anti-congestive amount of achemical compound selected from the group consisting of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedioneand the pharmaceutically acceptable acid-addition salts thereof.
 10. Ananticongestive composition according to claim 6 wherein Ar is an arlyradical, X is >C═O, Alk is an alkylene chain having 2 or 3 carbon atoms;and Q is connected to the alkylene side chain by the 2- or 3-position.11. A method of treating congestion in warm-blooded animals whichcomprises the administration thereto of an effective anticongestiveamount of a chemical compound selected from the group consisting of aquinazoline compound having the formula ##STR42## and thepharmaceutically acceptable acid addition salts thereof, wherein: Ar isa member selected from the group consisting of aryl, thienyl, andpyridinyl radicals;X is a member selected from the group consisting of##STR43## wherein said q is the integer 2 or 3; R is a member selectedfrom the group consisting of hydrogen, hydroxy and lower alkyl; Alk isan alkylene chain having from 1 to 4 carbon atoms; and Q is aquinazolinyl radical, the 1-, 2-, 3- or 4-position of which is connectedwith the alkylene side chain, said quinazolinyl radical bearing in oneor both of its 2- and 4-positions a oxo or thioxo group, wherein thebenzene ring of said quinazolinyl radical is optionally substituted with1 to 3 substituents each independently selected from the groupconsisting of halo, lower alkyl, lower alkyloxy, trifluoromethyl, nitroand cyano, and wherein the pyrimidino ring of said quinazolinyl radicalmay be partyly or fully saturated, said pyrimidino ring being optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of lower alkyl, aryl, aryl(loweralkyl), thienyl,pyridinyl, thienyl (loweralkyl), and pyridinyl (lower alkyl); whereinaryl as used in the definition of said Ar and of said Q is a memberselected from the group consisting of penyl and phenyl substituted withfrom 1 to 2 substituents each independently selected from the groupconsisting of halo, lower alkyl, lower alkyloxy, trifluoromethyl andamino.
 12. A method according to claim 11 wherein X is CO.
 13. A methodaccording to claim 12 wherein Alk is an 1,2-ethanediyl radical.
 14. Amethod of treating congestion in warm-blooded animals which comprisesthe administration thereto of an effective anti-congestive amount of achemical compound selected from the group consisting of3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione and the pharmaceutically acceptable acid additionsalts thereof.
 15. A method according to claim 11 wherein Ar is an arylradical, X is >C═O, Alk is an alkylene chain having 2 or 3 carbon atoms;and Q is connected to the alkylene said chain by the 2- or 3-position.